Self-adaptive (homeostatic) biological systems operate via repeated incremental feedback and feed forward signaling adjustments to maintain species, gender and age-defined physiological norms. Recent model-independent statistics forecast that one of the earliest detectable neuroendocrine adaptations in healthy aging is quantifiable failure of interactive (interglandular) signaling in the absence of overt hormone depletion (PNAS 93: 14100-05, 1996). According to an ensemble (servo mechanistic) concept of regulation both feedback and feed forward pathways mediate signal integration in closed physiological systems (PNAS 98: 4028-33, 2001). Unlike recent successful modeling of nonlinear feed forward (stimulatory) function in the uninfused human and experimental animal (PNAS 101: 6740-6745, 2004); no generalizable analytical methodology exists for parsing negative-feedback properties in vivo non-invasively. This major technical obstacle has precluded progress in dissecting mechanisms of adaptive control in interlinked biological systems in general. The analytical need is significant, because classical experimental and statistical strategies examine only a single locus of control after disabling other inputs. However, experimental isolation of any component of a system definitionally disrupts the ensemble interactions under study. Based upon this major need in the field, the present objectives are to: (1) develop an experimentally validated clinical paradigm of intermittent feedback signaling; and (2) create a statistically verified analytical formalism to quantitate time-varying signaling interactions in vivo without disrupting physiological mechanisms. The current proposal addresses these challenges by way of 2 Specific Aims: Aim I is to implement a clinical model of physiologically intermittent feedback signaling in a prototypical (hypothalamo-pituitary-gonadal) ensemble axis in 40 healthy men ages 18-80 yr. Aim II is to establish a novel analytic framework for quantitating in vivo feedback properties without disrupting the system under study. The clinical goal is to test the a priori hypothesis that age determines the potency, sensitivity and/or efficacy of androgen-mediated negative feedback. The technical expectation is to achieve a general tractable statistical construct to quantify nonlinear negative-feedback coupling (explicitly, reconstruct unobserved time-evolving inhibitory dose-response functions) from serial measurements of the output of a subset of nodes in the system. Creating a paradigmatic biomathematical platform for quantifying intermittent feedback signaling in the uninfused unblocked and unstimulated human and animal will have far-reaching implications in advancing investigations of early subtle adaptive failure in aging, stress and disease. Public Summary. Aging depletes the anabolic hormone, testosterone, which is a potent androgen in men and women. The basis for impoverished androgen availability in aging is not known, but clinical consequences include physical frailty, cognitive impairment and reduced quality of life. The present proposal develops a general biomathematical framework for dissecting otherwise observed pathways that control hormone output in aging, stress and disease. [unreadable] [unreadable] [unreadable]